RELATIONSHIP BETWEEN SHELTERIN PROTEINS AND AGMATINE IN URINARY TRACT INFECTIONS

Mustafa Doğan Bedir; Sevtap Bakır; Aynur Engin

doi:10.7197/cmj.1294625

EN TR

RELATIONSHIP BETWEEN SHELTERIN PROTEINS AND AGMATINE IN URINARY TRACT INFECTIONS

Abstract

Abstract: The presence of microorganisms in the kidney, collecting system, or bladder with pyuria and clinical symptoms is called Urinary Tract Infection (UTI). UTI is one of the most common diseases in both nosocomial and community-acquired infections and affects millions of people every year. The clinical types of UTI range from cystitis to sepsis. In this study, we aimed to contribute to the literature by comparing the levels of shelterin proteins and agmatine in the serum of patients diagnosed with cystitis, one of the types of UTI, and healthy volunteers without any known medical disorder, and to bring new approaches to issues such as clinical severity, response to treatment, and pathogenesis of the disease. Methods: In this study, 30 individuals diagnosed with cystitis from UTIs and 30 individuals without any systemic disease participated. Serum agmatine levels were measured by a fluorescence detector using the ultra-high-performance liquid chromatography method (UHPLC). Serum shelterin proteins levels were measured using the ELISA method. Results: When the patients and healthy controls were compared, serum Telomeric Repeat Binding Factor2 (TRF2) levels of the patients were found to be lower than the controls; serum agmatine levels were found to be higher than the controls and statistically significant (p<0.05). Other shelterin protein levels were not statistically different between patients and controls (p>0.05). Conclusion: In conclusion, the statistically significant difference in serum TRF2 and agmatine levels between the groups may be associated with oxidative stress. It is thought that the shortening of telomere lengths may be associated with decreased TRF2 levels.

Keywords

ÜRİNER SİSTEM ENFEKSİYONLARINDA SHELTERİN PROTEİNLERİ VE AGMATİN İLİŞKİSİ

Öz

Özet: Piyüri ve klinik semptomlarla birlikte böbrekte, toplayıcı sistemde veya mesanede mikroorganizmanın bulunması, Üriner Sistem Enfeksiyonu (ÜSE) olarak adlandırılır. ÜSE, hem nozokomyal enfeksiyonlar hem de toplumdan kazanılmış enfeksiyonlarda en sık rastlanan hastalıklar arasında yer almaktadır ve her yıl milyonlarca insanı etkilemektedir. ÜSE’nin klinik tipleri, sistitten sepsise kadar değişmektedir. Bu çalışmada, ÜSE türlerinden biri olan sistit tanısı almış hastalar ile bilinen herhangi bir tıbbi bozukluğu olmayan sağlıklı gönüllü kişilerin serumlarında, shelterin proteinleri ve agmatin düzeylerinin karşılaştırılarak hastalığın klinik ciddiyeti, tedaviye yanıt takibi, patogenezi gibi hususlara yeni yaklaşımlar getirilmesi ve literarüre katkı sağlanması amaçlanmıştır. Yöntemler: Bu çalışmada, ÜSE’lerden sistit tanısı almış 30 birey ve herhangi bir sistemik hastalığı olmayan 30 birey katılmıştır. Serum agmatin seviyeleri ultra yüksek performanslı sıvı kromatografi yöntemi (UHPLC) kullanılarak floresans dedektörle ölçülmüştür. Serum shelterin protein düzeyleri ise ELISA yöntemi kullanılarak ölçülmüştür. Bulgular: Hastalar ile sağlıklı kontroller karşılaştırıldığında, hastaların serum Telomerik Tekrar Bağlanma Faktörü2 (TRF2) düzeyleri kontrollere göre düşük; serum agmatin düzeyleri kontrolllere göre yüksek bulunmuştur ve istatistiksel olarak anlamlıdır (p<0,05). Diğer shelterin protein düzeyleri ise hasta ve kontrol arasında istatistiksel farklı hesaplanmamıştır (p>0,05). Sonuç: Sonuç olarak, serum TRF2 ve agmatin düzeylerinin gruplar arasında istatistiksel olarak anlamlı farklılık göstermesi oksidatif stres ile ilişkilendirilebilir. TRF2 düzeylerindeki azalma ile telomer uzunluklarında kısalma olabileceği düşünülmektedir.

Anahtar Kelimeler

Supporting Institution

SİVAS CUMHURİYET ÜNİVERSİTESİ BİLİMSEL ARAŞTIRMA PROJELERİ KOORDİNASYON BİRİMİ (CÜBAP)

Project Number

T-812

Thanks

Bu çalışma Sivas Cumhuriyet Üniversitesi Bilimsel Araştırma Projeleri Komisyonu tarafından T-812 numaralı doktora tez projesi kapsamında maddi olarak desteklenmiştir

References

1. Abreu, A. G., Marques, S. G., Monteiro-Neto, V., et al. (2013). Extended-spectrum β-lactamase-producing enterobacteriaceae in community-acquired urinary tract infections in São Luís, Brazil. Brazilian Journal of Microbiology, 44, 469-471.
2. Kunin, C. M. (1994). Urinary tract infections in females. Clinical Infectious Diseases, 18 (1), 1-10.
3. Stamm, W. E., Norrby, S. R. (2001). Urinary tract infections: disease panorama and challenges. The Journal of infectious diseases, 183, 1-4.
4. Kadanalı, A. (2006). Üriner sistem infeksiyonları. EAJM, 38, 119-123.
5. Uzbay, T. I. (2012). The pharmacological importance of agmatine in the brain. Neuroscience & Biobehavioral Reviews, 36 (1), 502-519.
6. Uzbay, T., Goktalay, G., Kayir, H., et al. (2013). Increased plasma agmatine levels in patients with schizophrenia. Journal of psychiatric research, 47 (8), 1054-1060.
7. Uzbay, T., Kayir, H., Goktalay, G., et al. (2010). Agmatine disrupts prepulse inhibition of acoustic startle reflex in rats. Journal of Psychopharmacology, 24 (6), 923-929.
8. Gilley, D., Tanaka, H., Herbert, B. S. (2005). Telomere dysfunction in aging and cancer. The international journal of biochemistry & cell biology, 37 (5), 1000-1013.

9. Xin, H., Liu, D., Songyang, Z. (2008). The telosome/shelterin complex and its functions. Genome biology, 9 (9), 1-7.
10. Wong, J. M., Collins, K. (2003). Telomere maintenance and disease. The Lancet, 362 (9388), 983-988. 11. Atlı, K., Bozcuk, A. N. (2002). Telomer ve hücresel yaşlanma. Geriatri, 5 (3), 111-114.
12. Rodier, F., Kim, S. H., Nijjar, et al. (2005). Cancer and aging: the importance of telomeres in genome maintenance. The international journal of biochemistry & cell biology, 37 (5), 977-990.
13. Neumann, A. A., Reddel, R. R. (2002). Telomere maintenance and cancer? look, no telomerase. Nature Reviews Cancer, 2 (11), 879-884.
14. Klapper, W., Parwaresch, R., Krupp, G. (2001). Telomere biology in human aging and aging syndromes. Mechanisms of ageing and development, 122 (7), 695-712.
15. Diotti, R., Loayza, D. (2011). Shelterin complex and associated factors at human telomeres. Nucleus, 2 (2), 119-135.
16. De Lange, T. (2011). How shelterin solves the telomere end-protection problem. In Cold Spring Harbor symposia on quantitative biology (pp. sqb-2010). Cold Spring Harbor Laboratory Press.
17. Kurtz, S., Shore, D. (1991). RAP1 protein activates and silences transcription of mating-type genes in yeast. Genes & development, 5 (4), 616-628.
18. Teo, H., Ghosh, S., Luesch, H., et al. (2010). Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression. Nature cell biology, 12 (8), 758-767.
19. Bayram, E., Çenesiz, M., Gümüşova, S. O. (2017). Viral Enfeksiyonlarda Telomeraz Aktivitesi. Harran Üniversitesi Veteriner Fakültesi Dergisi, 6 (1), 108-111.
20. Kamranvar, S. A., Chen, X., Masucci, M. G. (2013). Telomere dysfunction and activation of alternative lengthening of telomeres in B-lymphocytes infected by Epstein–Barr virus. Oncogene, 32 (49), 5522-5530.
21. Grill, S., Tesmer, V. M., Nandakumar, J. (2018). The N terminus of the OB domain of telomere protein TPP1 is critical for telomerase action. Cell reports, 22 (5), 1132-1140.
22. Najar, M. S., Saldanha, C. L., Banday, K. A. (2009). Approach to urinary tract infections. Indian journal of nephrology, 19 (4), 129.
23. FCSHP, B. A. I. By Helen S. Lee, Pharm. D., et al. (2018). Urinary Tract Infections PSAP 2018 BOOK Infectious Diseases
24. De Lange, T. (2005). Shelterin: the protein complex that shapes and safeguards human telomeres. Genes & development, 19 (18), 2100-2110.
25. Schmutz, I., de Lange, T. (2016). Shelterin. Current Biology, 26(10), R397-R399.
26. Hu, H., Zhang, Y., Zou, M., et al. (2010). Expression of TRF1, TRF2, TIN2, TERT, KU70, and BRCA1 proteins is associated with telomere shortening and may contribute to multistage carcinogenesis of gastric cancer. Journal of cancer research and clinical oncology, 136 (9), 1407-1414.
27. Zheng, J. (2012). Isotope Labeling Liquid Chromatography Mass Spectrometry: Metabolite Identification and Human Salivary Metabolome Profiling. University of Alberta (Canada).
28. Barua, S., Kim, J. Y., Kim, J. Y., et al. (2019). Therapeutic effect of agmatine on neurological disease: focus on ion channels and receptors. Neurochemical research, 44 (4), 735-750.
29. Atanassov, B. S., Evrard, Y. A., Multani, et al. (2009). Gcn5 and SAGA regulate shelterin protein turnover and telomere maintenance. Molecular cell, 35 (3), 352-364.
30. Kabir, S., Hockemeyer, D., de Lange, T. (2014). TALEN gene knockouts reveal no requirement for the conserved human shelterin protein Rap1 in telomere protection and length regulation. Cell reports, 9 (4), 1273-1280.
31. Nijjar, T., Bassett, E., Garbe, J., et al. (2005). Accumulation and altered localization of telomere-associated protein TRF2 in immortally transformed and tumor-derived human breast cells. Oncogene, 24 (20), 3369-3376.
32. Biroccio, A., Rizzo, A., Elli, R., et al. (2006). TRF2 inhibition triggers apoptosis and reduces tumourigenicity of human melanoma cells. European Journal of Cancer, 42 (12), 1881-1888.
33. Chen, X. H., Tong, Y., Xu, et al. (2008). Expression of telomere binding factor 2 (TRF2) on leukemia cell lines and primary leukemia cells. Zhejiang da xue xue bao. Yi xue ban= Journal of Zhejiang University. Medical Sciences, 37 (2), 170-175.
34. Buscemi, G., Zannini, L., Fontanella, E., et al. (2009). The shelterin protein TRF2 inhibits Chk2 activity at telomeres in the absence of DNA damage. Current Biology, 19 (10), 874-879.
35. Gilbert-Girard, S., Gravel, A., Collin, V., et al. (2020). Role for the shelterin protein TRF2 in human herpesvirus 6A/B chromosomal integration. PLoS pathogens, 16 (4), e1008496.
36. Victor, J., Deutsch, J., Whitaker, A., et al. (2021). SARS-CoV-2 triggers DNA damage response in Vero E6 cells. Biochemical and biophysical research communications, 579, 141-145.
37. Erşan, S., Kurt, A. (2020). Şizofreni Hastalarında Shelterin Kompleksi Düzeylerinin Sağlıklı Bireylerle Karşılaştırılması̇ (Vol. 2). Vol. 2. International Journal of Academic Medicine and Pharmacy.
38. Mishra, S., Kumar, R., Malhotra, et al. (2016). Mild oxidative stress is beneficial for sperm telomere length maintenance. World journal of methodology, 6 (2), 163.
39. Erdel, F., Kratz, K., Willcox, S., et al. (2017). Telomere recognition and assembly mechanism of mammalian shelterin. Cell reports, 18 (1), 41-53.
40. Liu, D., O'Connor, M. S., Qin, et al. (2004). Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. Journal of Biological Chemistry, 279 (49), 51338-51342.
41. Kim, S. H., Davalos, A. R., Heo, S. J., et al. (2008). Telomere dysfunction and cell survival: roles for distinct TIN2-containing complexes. The Journal of cell biology, 181 (3), 447-460.
42. De Lange, T. (2018). Shelterin-mediated telomere protection. Annu. Rev. Genet, 52 (1), 223-247.
43. Li, B., Oestreich, S., De Lange, T. (2000). Identification of human Rap1: implications for telomere evolution. Cell, 101 (5), 471-483.
44. Kao, H. T., Cawthon, R. M., Delisi, L. E., B et al. (2008). Rapid telomere erosion in schizophrenia. Molecular psychiatry, 13 (2), 118-119.
45. O'Connor, M. S., Safari, A., Liu, D., et al. (2004). The human Rap1 protein complex and modulation of telomere length. Journal of Biological Chemistry, 279 (27), 28585-28591.
46. Xin, H., Liu, D., Wan, M., et al. (2007). TPP1 is a homologue of ciliate TEBP-β and interacts with POT1 to recruit telomerase. nature, 445 (7127), 559-562.
47. Kaminker, P. G., Kim, S. H., Desprez, P. Y., et al. (2009). A novel form of the telomere-associated protein TIN2 localizes to the nuclear matrix. Cell cycle, 8 (6), 931-939.
48. Gümrü, S., Şahin, C., Arıcıoğlu, F. (2013). Yeni bir nörotransmitter/ nöromodülatör olarak agmatine genel bir bakış. Clinical and Experimental Health Sciences, 3 (5), 523-528.
49. El-Kashef, D. H., El-Kenawi, A. E., Rahim, M. A., et al. (2016). Agmatine improves renal function in gentamicin-induced nephrotoxicity in rats. Canadian Journal of Physiology and Pharmacology, 94 (3), 278-286. 50. Galea, E., Regunathan, S., Eliopoulos, et al. (1996). Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. Biochemical Journal, 316 (1), 247-249.
51. Gregson, D. B., Wildman, S. D., Chan, C. C., et al. (2021). Metabolomics strategy for diagnosing urinary tract infections. medRxiv, 1-21.
52. Lewis, I. A., Gregson, D., Groves, R. (2021). U.S. Patent Application No. 15/734,163.
53. Galea, E., Regunathan, S., Eliopoulos, et al. (1996). Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. Biochemical Journal, 316 (1), 247-249.
54. Meotti, F. C., Stangherlin, E. C., Zeni, G., et al. (2004). Protective role of aryl and alkyl diselenides on lipid peroxidation. Environmental Research, 94 (3), 276-282.
55. Hensley, K., Robinson, K. A., Gabbita, S. P., et al. (2000). Reactive oxygen species, cell signaling, and cell injury. Free Radical Biology and Medicine, 28 (10), 1456-1462.
56. Piletz, J. E., May, P. J., Wang, G., et al. (2003). Agmatine crosses the blood‐brain barrier. Annals of the New York Academy of Sciences, 1009 (1), 64-74.
57. Zhu, M. Y., Iyo, A., Piletz, J. E., et al. (2004). Expression of human arginine decarboxylase, the biosynthetic enzyme for agmatine. Biochimica et Biophysica Acta (BBA)-General Subjects, 1670 (2), 156-164.
58. Kendellen, M. F., Barrientos, K. S., Counter, C. M. (2009). POT1 association with TRF2 regulates telomere length. Molecular and cellular biology, 29 (20), 5611-561

Details

Primary Language

English

Subjects

Health Care Administration

Journal Section

Research Article

Authors

Mustafa Doğan Bedir ^*
0000-0002-2628-0739
Türkiye

Sevtap Bakır
0000-0003-1956-0844
Türkiye

Aynur Engin
0000-0002-8533-8793
Türkiye

Publication Date

December 31, 2023

Submission Date

May 9, 2023

Acceptance Date

December 14, 2023

Published in Issue

Year 1970 Volume: 45 Number: 4

DOI

https://doi.org/10.7197/cmj.1294625

IZ

https://izlik.org/JA33NS85YB

Cite

RIS / Bibtex

AMA

1.Bedir MD, Bakır S, Engin A. RELATIONSHIP BETWEEN SHELTERIN PROTEINS AND AGMATINE IN URINARY TRACT INFECTIONS. CMJ. 2023;45(4):26-35. doi:10.7197/cmj.1294625